Abstract This application requests renewal of a randomized controlled trial (R01NR007755) whose aim was to evaluate the short and long-term efficacy of a brief psychosocial/behavioral intervention (with adjunctive antidepressant) for the treatment of post-stroke depression (PSD) in survivors of ischemic stroke. We have demonstrated that a pleasant event/problem-solving brief psychosocial-behavioral therapy delivered by psychosocial nurse practitioners is highly effective in treating major depression and promoting remission in ischemic stroke survivors for up to two years and that carrying one or more 5-HTTLPR s-alleles, a serotonin transporter gene polymorphism, was associated not only with a greater risk of PSD, but also with the greatest reduction in depressive symptoms for the psychosocial intervention. In this renewal we seek to replicate this finding in a larger sample. We also want refine the protocol, and potentially make it more cost effective, by conducting a randomized comparative effectiveness trial of in-person versus telephone delivery of the intervention, comparing with usual care control. Finally, we seek to expand our sample to include hemorrhagic stroke survivors as well as those with ischemic stroke. 225 people within 3 months of ischemic or hemorrhagic stroke and who are clinically depressed will be randomized into a pleasant events/problem-solving brief psychotherapy in person (n=75) or by telephone (n=75) or into a usual care control group (N=75). Consistent with standard of care in the community, all participants will be prescribed an antidepressant by their primary caregiver. The primary outcome is remission (Hamilton Rating Scale for Depression score < 10), with treatment response (50% or greater reduction in HDRS) a secondary endpoint. We will explore the contribution of age, gender, stroke type and genetic variation to treatment response and remission. The ability to identify a relatively simple way, i.e. by genotyping, those who will benefit most from brief psychosocial-behavioral therapy will be a major breakthrough in personalized treatment of depression in chronic illness. In addition, the comparison of two modes of delivering this brief psychosocial-behavioral therapy treatment will provide additional information about cost-effective means to integrate this intervention in everyday practice.